Individuals vary in their expression of complex traits. This is true even when they share the same genotype at loci that determine a trait across the population. Environmental factors contribute to the variation in expression. Here, we ask whether genes play a role in the individual variation in expression of a complex trait when environmental differences are excluded. The complex trait we employ to examine this question is the replicative lifespan of the yeast Saccharomyces cerevisiae. Our preliminary studies show that there exist quantitative trait loci that are associated with the characteristic heterogeneity of lifespans independent of genetic variation that determines longevity, and we have narrowed this genetic variation down to a single causal gene at one of these quantitative trait loci. This leads to the proposed study. First, we will examine the development during the lifespan of five separate phenotypes that represent functional decline at the cellular, subcellular, and molecular levels, in strains possessing alternate variants of this gene that are responsible for heterogeneity in lifespan. This tests the hypothesis that the kinetics of expression of one or more of these phenotypes is associated with the individual variation in lifespan. Second, we will dissect the molecular mechanism(s) that that are responsible for the expression profiles of these phenotypes and for the heterogeneity in lifespan. This will involve a hypothesis-driven approach based on the several known interactions and functions of this gene. Third, we will institute a genome-wide screen for loci that are associated with the development of the five aspects of functional decline during the lifespan. This will test the notion that there exists a global phenotype associated with individual variation in lifespan. Multivariate approaches will be applied to elaborate patterns of functional decline associated with both high and low individual variation in lifespan. This project has broad application across biomedicine because of its potential to identify novel factors important for stem cell function and tissue homeostasis.